den Hollander J, Rimpi S, Doherty JR, Rudelius M, Buck A, Hoellein A et al.. Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state. Blood 116: 1498-1505

III Medical Department, Technische Universität München, Munich, Germany.
Blood (Impact Factor: 10.45). 09/2010; 116(9):1498-505. DOI: 10.1182/blood-2009-11-251074
Source: PubMed


Myc oncoproteins promote continuous cell growth, in part by controlling the transcription of key cell cycle regulators. Here, we report that c-Myc regulates the expression of Aurora A and B kinases (Aurka and Aurkb), and that Aurka and Aurkb transcripts and protein levels are highly elevated in Myc-driven B-cell lymphomas in both mice and humans. The induction of Aurka by Myc is transcriptional and is directly mediated via E-boxes, whereas Aurkb is regulated indirectly. Blocking Aurka/b kinase activity with a selective Aurora kinase inhibitor triggers transient mitotic arrest, polyploidization, and apoptosis of Myc-induced lymphomas. These phenotypes are selectively bypassed by a kinase inhibitor-resistant Aurkb mutant, demonstrating that Aurkb is the primary therapeutic target in the context of Myc. Importantly, apoptosis provoked by Aurk inhibition was p53 independent, suggesting that Aurka/Aurkb inhibitors will show efficacy in treating primary or relapsed malignancies having Myc involvement and/or loss of p53 function.

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Available from: Joanne Doherty, Nov 04, 2014
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    • "Notably, >90% of cancers overexpress or overactivate AURKA at some level, and this outcome can be mediated directly by oncogene expression (den Hollander et al. 2010; Lens et al. 2010). According to our studies, accentuated AURKA–PLK1 pathway activity may promote replication fork collapse and an increased dependence on ATR function. "
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    • "Furthermore, there is evidence that c-Myc is involved in polyploidisation of normal mouse hepatocytes; in particular it was shown that c-Myc accelerates hepatic ploidy in transgenic mouse models [112]. c-Myc also up-regulates Aurora B kinase [113] which is implicated in the maintenance of the malignant state and in mitotic slippage [48]; all effects which could contribute to the induction and maintenance of reversible polyploidy. Therefore, the switch to a glycolytic metabolism involving constitutional activation of c-Myc can be suggested as a key molecular event linking reversible polyploidy to stemness, immortality, and likely EMT phenotype of depolyploidised descendants and as a means of shifting from senescence towards cancer progression. "
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